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FOUNOCO  BY  JOHN  O.  ROCKKPELLKR 


RECAP 


CUTANEOUS  ALLERGY  IN  GONO- 
COCCAL INEECTIONS 


A  DISSERTATION 

SUBMITTED    TO    THE    FACULTY    OF    THE    OGDEN    GRADUATE    SCHOOL     OF 

SCIENCE    IN    CANDIDACY    FOR    THE    DEGREE    OF 

DOCTOR    OF    PHILOSOPHY 

(departaient  of  bacteriology) 


BY 
ERNEST  EDWARD  IRONS 


CHICAGO,  ILLINOIS 
1912 


Reao2 


lEi^ 


College  of  ^fjPisicians  anh  burgeons 
ILibtavp 


Digitized  by  the  Internet  Archive 

in  2010  with  funding  from 

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http://www.archive.org/details/cutaneousallergyOOiron 


Ubc  xaniverstti?  of  Cbicago 

FOUNDED   BY  JOHN   D.   ROCKEFELLER 


CUTANEOUS  ALLERGY  IN  GONO- 
COCCAL INEECTIONS 


A  DISSERTATION 

SUBMITTED    TO    THE    FACULTY    OF    THE    OGDEN    GRADUATE    SCHOOL     OF 

SCIENCE    IN    CANDIDACY    FOR    THE    DEGREE    OF 

DOCTOR    OF    PHILOSOPHY 

(department  of  bacteriology) 


BY 
ERNEST  EDWARD  IRONS 


CHICAGO,  ILLINOIS 
1912 


CUTANEOUS  ALLERGY  IN  GONOCOCCAL  INFECTIONS.* 

Ernest  E.   Irons. 

{From  the  Memorial  Inslilule  for  Infeclious  Diseases,  Chicago.) 

The  inoculation  of  the  gonococcus  into  the  body  of  man  or 
animals  causes  changes  in  the  blood  which  have  been  demonstrated 
by  studies  of  the  specific  agglutinins,  precipitins,  and  opsonins. 
More  recently  the  antibody  content  of  the  serum  has  been  esti- 
mated by  means  of  complement  fixation,  using  preparations  of  the 
gonococcus  as  antigen.  By  all  these  methods,  the  variations  in 
the  course  of  gonococcal  infection  may  be  more  or  less  satisfactorily 
followed,  and,  in  the  case  of  the  opsonins  at  least,  the  curve  of 
immunity  may  be  correlated  with  the  changes  in  the  clinical  course 
of  the  disease. 

Certain  reactions,  also,  follow  the  subcutaneous  inoculation  of 
suspensions  of  killed  gonococci  in  patients  suffering  from  gonococcal 
infection.  These  reactions  are  characteristic^  and  are  analogous 
to  those  seen  after  the  injection  of  tuberculin,  mallein,  etc.,  in  the 
respective  diseases.  At  the  site  of  the  inoculation  there  appears 
after  a  few  hours,  an  area  of  redness,  swelling,  and  tenderness,  from 
2  cm.  to  6  cm.  or  more  in  diameter,  depending  upon  the  amount 
of  the  suspension  inoculated.  Sometimes  the  whole  upper  arm 
becomes  swollen  and  painful.  After  24  to  48  hours  the  reaction 
subsides.  There  is  frequently  an  increase  in  pain  and  sometimes 
swelling  in  the  affected  joints  or  other  locahzations,  together  with 
general  symptoms  of  malaise,  headache,  and  fever.  An  increase 
in  leukocytosis  may  occur. 

The  degree  of  the  reaction  varies  in  different  cases  with  the 
extent  of  the  infection  and  the  general  condition  of  the  patient. 
In  gonococcal  arthritis  in  which  active  symptoms  have  been  absent 
for  some  time,  a  subcutaneous  inoculation  may  produce  httle  more 
than  a  local  reaction  at  the  site  of  the  injection.  In  chronic  t\T)es 
of  arthritis  in  which  there  have  been  repeated  severe  attacks  of  the 

*  Received  for  publication  May  23,  1912. 
'  Jour.  Inject.  Dis.,  1908,  5,  p.  270. 

77 


78  Ernest  E.  Irons 

infection,  the  reaction  may  be  very  slight  or  absent.  These  cases 
often  do  badl>-  under  \-accine  treatment.  In  cases  in  which 
repeated  inoculations  are  made  for  therapeutic  purposes,  the 
reactions  usually  grow  less  with  successive  doses  of  the  same  size. 
Patients  who  have  received  a  number  of  inoculations  of  moderate 
doses,  without  exhibiting  more  than  a  sHght  reaction,  occasionally 
show  a  pronounced  reaction  after  an  inoculation  of  the  same  size, 
given  in  the  same  way  as  previous  doses. 

Ocular  reactions  following  inoculations  are  sometimes  observed 
in  cases  in  which  iritis  has  previously  been  present.  A  man  of  35 
who  had  suffered  from  arthritis  and  iritis  six  years  previously 
complained  of  pain  in  the  joints  of  the  spine  and  ankles.  There 
had  been  no  recent  active  trouble  in  the  eye.  He  was  given  a 
subcutaneous  inoculation  of  100  million  gonococci  for  diagnostic 
purposes.  Twenty-four  hours  later  the  previously  affected  eye 
became  painful:  photophobia  and  some  conjunctival  injection 
were  present.  The  other  eye  showed  no  change.  The  symptoms 
subsided  after  24  hours.  Reactions  characterized  by  increased  in- 
flammation, or  by  effusions  in  the  eye,  are  not  infrequent  after 
therapeutic  inoculations  of  vaccine  in  active  gonococcal  iritis.  In  a 
number  of  cases,  however,  such  reactions  have  been  entirely 
absent,  even  after  large  doses  of  vaccine. 

The  degree  of  reaction  depends  not  only  on  the  number  of  gono- 
cocci inoculated,  but  also  on  the  source  and  age  of  the  cultures  from 
which  the  vaccine  is  prepared.  Recently  isolated  cultures  (two 
weeks  to  three  months,  fifth  to  40th  generation)  furnished  a  vaccine 
10  times  as  strong  as  a  culture  which  had  been  grown  in  the  labora- 
tory for  two  years.  This  variability  in  the  activity  of  vaccines 
may  explain  the  dift'erences  of  opinion  as  to  the  optimum  thera- 
peutic dose  of  gonococcal  vaccine. 

The  reaction  has  a  diagnostic  value  in  obscure  cases  of  arthritis, 
and  its  use  has  also  been  suggested  for  the  determination  of  the 
cure  of  local  gonococcal  infections.  Bruck^  has  observed  the  reac- 
tion in  epididymitis,  and  Reiter-  in  pelvic  infections  in  women,  and 
in  arthritis. 

■  Deutsche  med.  Wchnschr.,  igog,  3s,  p.  470. 

» Zlschr.f.  Geburlsh.  u.  Khiderh.,  1911,  68,  p.  471. 


Cutaneous  Allergy  in  Gonococcal  Infections         79 

CUTANEOUS   ALLIORGY. 

The  cutaneous  reaction  to  injections  of  preparations  of  the  gono- 
coccus  has  been  studied  by  several  workers.  Bruck'  obtained  a 
"cutireaction"  by  intradermal  inoculation  of  gonococcal  vaccines. 
Kohler^  inoculated,  by  the  method  of  von  Pirquet,  vaccines  pre- 
pared from  streptococcus,  gonococcus,  colon  bacillus,  etc.,  and  was 
able  to  demonstrate  the  specificity  of  the  reaction  in  cases  of  gono- 
coccal infection. 

In  recent  experiments  with  glycerin  extracts  of  the  gonococcus, 
I  have  found  that  a  well  defined  cutaneous  reaction,  similar  to  the 
cutaneous  tuberculin  reaction,  occurs  in  cases  of  gonococcal  infec- 
tion, when  the  extract  is  introduced  into  the  skin  by  the  method  of 
von  Pirquec,  and  that  the  course  of  the  immunity  curve  in  a  given 
case  may  be  traced  from  day  to  day  by  noting  the  degree  of  the  reac- 
tion after  successive  inoculations.  These  curves  are  similar  to  those 
obtained  by  daily  estimations  of  the  opsonic  index,  and  their 
fluctuations  may  be  correlated  with  the  clinical  changes  observed 
in  the  patient.  In  recently  infected  cases,  the  cutaneous  allergy 
is  seen  to  increase  steadily  from  day  to  day. 

PREPARATION    OF    MATERIAL    FOR    TESTS    OF    CUTANEOUS    ALLERGY. 

Cultures  of  strains  of  the  gonococcus  were  grown  on  ascites  agar 
for  24  hours,  the  growth  removed  with  sterile  distilled  water,  0.5 
per  cent  phenol  added,  and  the  suspensions  placed  at  37°  C.  for 
48  hours.  The  fluid  was  then  heated  to  60°  C.  for  two  hours,  glycerin 
added,  and  the  mixture  evaporated  in  a  current  of  warm  air.  The 
final  product  was  a  clear  yellowish  fluid  of  the  consistence  of  glycerin. 
In  the  following  discussion  it  will  be  referred  to  as  "gonococcin"' 
in  conformity  with  the  terminology  of  other  similar  products,  such 
as  tuberculin,  leprolin,  tricophytin,  luetin,  etc. 

The  technic  briefly  described  has  been  modified  in  various  wa}-s 
in  the  course  of  the  work,  without  essentially  changing  the  results. 
Human  blood  agar  as  a  culture  medium  was  substituted  for  ascites 
agar  without  changing  the  action  of  the  final  product.  Xo  differ- 
ence was  noted  in  the  products  when  normal  salt  solution  was  used 

'Loc.  cit. 

'Wien.  klin.  Wchnschr.,  igii,  24,  p.  1564. 


So  Ernest  E.  Irons 

in  place  of  distilled  water  for  making  the  suspensions,  and  the  latter 
was  adopted  to  avoid  the  possible  irritant  action  of  the  salt  in  the 
concentrated  product. 

Material  for  control  inoculation  was  prepared  in  precisely  the 
same  manner,  using  the  washing  from  the  same  number  of  unin- 
oculated  culture  tubes. 

Cultures  from  five  strains  of  gonococci  were  combined  in  the 
antigen  used  in  most  of  these  cutaneous  tests.  Experiments  with 
antigens  made  from  single  strains  showed  that  in  some  instances 
the  reaction  from  one  of  the  strains  was  less  than  that  from  the 
others.  The  strains  used  were  derived  from  cases  of  arthritis  and 
urethritis.  In  a  case  of  vaginitis  and  ophthalmia  an  autogenous 
antigen  gave  the  same  degree  of  reaction  as  did  the  stock  antigen 
of  three  combined  strains. 

Cultures  of  the  gonococcus  from  24-hour  blood  agar  transfers 
were  planted  on  large  tubes  (2.5  cm.Xis  cm.)  of  slanted  ascites 
agar  and  incubated  for  24  hours.  Care  was  taken  that  the  seeding 
of  the  surface  of  the  slants  was  uniform,  and  drying  of  the  surface 
was  prevented  by  cork  stoppers  in  the  tubes.  The  suspension 
obtained  from  six  tubes  was  used  in  the  preparation  of  i  c.c.  of  the 
final  product. 

A  somewhat  more  exact  method  of  preparing  the  antigen  was 
attempted  by  evaporating  a  suspension  to  dryness,  and  then  taking 
up  the  weighed  powdered  residue  in  glycerin.  This  residue  neces- 
sarily contained  some  soluble  products  from  the  culture  medium, 
in  addition  to  substances  derived  from  the  gonococcus.  Serial 
dilutions  of  this  extract  were  prepared,  and  the  reactions  obtained 
with  them  compared  with  the  reactions  from  the  extract  prepared 
by  the  first  method.  It  was  found  that  an  extract  containing  o .  i 
gm.  of  the  powdered  residue  in  i  c.c.  of  glycerin  gave  approximately 
the  same  degree  of  reaction  as  did  the  extract  prepared  by  the  first 
method.  The  reactions  were  progressively  less,  the  greater  the 
dilution  of  the  gonococcin.  A  dilution  of  the  extract  containing 
o.ooi  gm.  per  c.c.  of  glycerin  gave  a  faint  reaction  in  allergic 
indi\'iduals. 

The  time  allowed  for  autolysis  of  the  suspensions  of  the  gono- 
coccus seemed  to  affect  the  strength  of  the  gonococcin.    An  antigen 


Cutaneous  Allergy  in  Gonococcal  Infections         8i 

prepared  from  a  suspension  of  gonococci  heated  to  60"^  C.  immedi- 
ately after  removal  of  the  organisms  from  the  surface  of  the  cul- 
ture medium  did  not  give  quite  as  strong  reactions  in  gonococcal 
cases  as  did  an  antigen  prepared  from  the  same  suspension  and 
kept  at  37°  C.  for  48  hours  before  heating  to  60°  C.  In  cases  in 
which  the  cutaneous  allergy  was  highly  developed,  the  difference 
between  the  two  antigens  was  absent. 

A  suspension  of  gonococci  was  evaporated  to  dryness,  and 
the  residue  extracted  for  48  hours  with  95  per  cent  alcohol.  An 
antigen  prepared  by  evaporating  the  alcoholic  extract  and  adding 
a  suitable  amount  of  glycerin  gave  only  a  slight  reaction  in  allergic 
persons.  The  residue  remaining  after  extraction  by  alcohol  was 
extracted  vdth  water  for  24  hours.  An  antigen  prepared  from  this 
extract  gave  a  good  reaction  in  susceptible  individuals. 

METHOD    OF   INOCULATION. 

The  preparations  of  gonococcin  and  the  control  extract  were 
kept  in  a  battery  of  cork-stoppered  vials.  A  separate  needle 
was  used  for  each  preparation.  Wlien  not  in  use,  the  needles  were 
kept  in  vials  of  alcohol,  each  corresponding  to  a  vial  of  antigen. 
In  this  way  each  needle  was  sterile,  and  used  only  for  its  own  antigen. 

Inoculations  were  made  by  gently  rotating  the  point  of  the 
needle  with  a  minute  drop  of  antigen  attached  on  the  skin  of  the 
arm.  Care  was  taken  to  avoid  the  puncture  of  capillaries.  In  all 
cases  a  series  of  at  least  three  inoculations  and  one  control  was 
made,  care  being  taken  to  make  the  inoculations  as  nearly  uniform 
as  possible. 

THE    CUTANEOUS   REACTION. 

The  cutaneous  reaction  after  the  inoculation  of  gonococcin  in 
infected  individuals  does  not  differ  essentially  from  that  following 
the  inoculation  of  other  antigens  such  as  tuberculin.  Within  a 
few  minutes  small  wheals  may  appear  about  the  point  of  puncture 
of  both  antigen  and  control.  After  a  few  hours  a  papule  is  formed, 
with  a  surrounding  area  of  hyperemia,  and  in  24  hours  the  maxi- 
mum reaction  is  usually  obtained.  On  the  second  day  the  h}"per- 
emia  is  less,  and  by  the  third  day  has  usually  disappeared.  The 
papules  remain  for  several  days,  and  in  pronounced  reactions  may 


Sz  Ernest  E.  Irons 

be  visible  seven  to  lo  days  after  inoculation.     Delayed  reactions 
have  not  been  observed. 

The  control  inoculation  shows  only  a  minute  point  at  the  site 
of  trauma. 

The  degree  of  the  reaction  in  gonococcal  infections  varies  with 
the  extent  of  the  infection,  and  from  time  to  time  in  the  same  case. 
Tvpical  reactions  in  gonococcal  arthritis  or  epididymitis  show  a 
papule  3  to  5  mm.  in  diameter,  with  a  surrounding  hyperemia  of 
7  to  lo  mm.  or  more.  Reactions  of  less  degree  were  frequently 
observed  in  known  gonococcal  infections  either  early  in  the  infec- 
tion or  later  in  the  course  of  the  disease. 

Normal  adults  in  whom  previous  gonococcal  infection  was 
excluded  showed  a  lesion  rarely  more  than  1-2  mm.  in  total  diameter. 
Often  the  points  of  puncture  showed  nothing  more  than  the  con- 
trol. Adults  suffering  from  other  diseases,  such  as  typhoid  fever, 
tuberculosis  of  bones  and  pleura,  staphylococcus  infections  (furun- 
culosis,  osteomyelitis),  leukemia,  lobar  pneumonia,  etc.,  in  whom 
previous  gonococcal  infection  was  excluded  gave  no  more  reaction 
than  the  average  normal  adult. 

For  the  purposes  of  discussion  the  reactions  obtained  in  this 
study  have  been  classified  as  positive  when  over  5  mm.  in  total 
diameter,  as  negative  when  3  mm.  or  less,  and  doubtful  when  the 
papule  was  small  and  the  hyperemia  indefinite  or  less  than  5  mm.  in 
diameter.  This  division,  though  arbitrary,  is  based  on  tests  in  a 
large  number  of  normal  and  infected  individuals,  using  antigens 
prepared  in  the  manner  indicated,  and  offers  a  convenient  solution 
of  the  difficulty  of  discussing  the  differences  in  cutaneous  reactivity 
of  the  cases  studied. 

In  children  in  whom  there  is  no  history  of  gonococcal  infection, 
about  50  per  cent  give  no  more  reaction  with  gonococcin  than  with 
the  control.  In  a  number  of  the  remainder  a  small  area  of  hyper- 
emia 2-3  mm.  in  diameter  is  obtained,  and  in  a  few,  larger  areas 
up  to  5  mm.,  rarely  7  mm.,  are  seen.  This  increased  cutaneous 
sensitiveness  in  children  has  been  observed  in  other  infections,  and 
has  been  explained  by  some  on  the  ground  that  in  children  the 
amount  of  normal  antibodies  is  proportionately  larger  than  in 
adults.     In  children  as  in  adults  the  increase  in  reactivity  may  be 


Cutaneous  Allkroy  in  Gonococcal  Infections         83 

observed  in  successive  tests  during  the  course  of  the  infectifjn,  and 
a  child  whose  skin  gives  a  reaction  of  1-2  mm.  at  the  beginning 
of  the  disease,  after  two  or  three  weeks,  may  give  a  ])ronounced 
reaction  of  7-8  mm.  The  possible  influence  of  infections  of  the 
nasal  passages  of  these  children  by  organisms,  closely  allied  to  the 
gonococcus,  such  as  M.  catarrhalis,  must  also  be  considered.  The 
question  of  a  group  reaction  will  be  discussed  later. 

Observations  on  patients  with  gonococcal  infections  soon  demon- 
strated that  while  the  ^degree  of  reaction  may  remain  fairly  con- 
stant from  day  to  day,  it  is  much  niore  frequent  for  the  reaction 
to  vary  in  intensity  from  time  to  time. 

The  diameter  in  millimeters  of  the  zone  of  hyperemia  surrounding 
each  papule  was  recorded  24  hours  after  inoculation.  The  results 
from  three  simultaneous  inoculations  were  averaged,  and  this 
average  used  in  plotting  curves  to  show  the  fluctuations  of  the 
reaction  in  a  given  case.  As  a  rule  there  was  no  marked  difference 
between  the  three  inoculations. 

The  daily  inoculation  of  even  minute  quantities  of  the  prepara- 
tions may  have  produced  a  slight  sensitization,  but  this  was  appar- 
ently very  small  compared  to  the  much  larger  influence  of  the 
infection  in  the  body. 

In  cases  in  which  it  was  desired  to  study  the  development  of 
immunity  in  infections  unmodified  by  treatment,  tests  were  made 
at  intervals  of  three  or  four  days. 

The  danger  of  confusion  in  the  reactions  through  the  produc- 
tion of  antibodies  by  the  albuminous  constituents  of  the  culture 
media  was  obviated  by  the  use  of  the  control  inoculation. 

The  hyperemia  resulting  from  the  occasional  infection  of  the 
point  of  inoculation  of  the  antigen  or  control  must  be  distinguished 
from  a  true  reaction.  Such  infections  usually  show  a  minute  white 
central  area  of  pus  formation.  Careful  preliminary  cleansing  of  the 
skin  with  alcohol,  and  the  making  of  multiple  inoculations  of  each 
antigen  will  usually  obviate  this  difficulty. 

THE    DEVELOPMENT    OF    CUTANEOUS    ALLERGY. 

Several  cases  of  recent  vaginitis  in  children  in  which  the  date  of 
first  discharge  was  known  were  tested  at  intervals  of  four  to  live 


84 


Ernest  E.  Irons 


days.  In  all.  the  reaction  in  the  first  week  was  negative  (i.e.,  there 
was  no  more  reaction  than  occurs  in  normal  individuals).  In  the 
second  and  third  weeks,  the  papules  became  slightly  larger,  and  by 
the  l\)urlh  week  pronounced  papules  with  surrounding  hyperemia 
were  noted. 

In  epididymitis  accompanying  gonorrhea,  the  reaction  varied 
in  the  cases  studied.  In  several,  tested  on  the  third  or  fourth  day 
of    the    epidid>'mitis,    cutaneous    reaction    was    pronounced.     In 


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Chart  i. — Cutaneous  allergy  with  respect  to  gonococcal  extracts  in  a  man  20  years  old;  first  attack 
of  gonorrhea  in  September,  1910;  recurrence  in  August,  191 1;  arthritis  in  October,  191 1;  no  discharge  at 
present;  now  suffers  from  tender  heels  and  ankles,  and  recurrent  hydrops  of  right  wrist  with  7  days'  cycle. 
Injections  of  killed  gonococci  as  shown  on  the  chart. 

two  cases  the  reaction  was  faint  on  the  second  and  third  days,  but 
by  the  fifth  day,  when  the  patient  had  begun  to  mend,  the  reaction 
became  more  definite. 

In  arthritis,  the  degree  of  the  reaction  varied  greatly.  In  several 
cases  of  extensive  arthritis,  the  reaction  was  negative  or  slight. 
Later,  when  improvement  in  general  condition  occurred,  the  cutane- 
ous reaction  became  pronounced.  In  one  case  of  extensive  arthri- 
tis, in  which  improvement  did  not  occur  while  under  observation,  a 
positive  reaction  was  not  obtained. 

In  infected  individuals  giving  a  weak  cutaneous  reaction,  the 
reaction  may  become  positive  on  a  second  test  after  the  inoculation 
of  gonococcus  vaccine  (Chart  i^. 

'  The  curves  shown  in  these  charts  were  constructed  from  successivi  determinations  of  the  degree  of 
cutaneous  reaction  following  the  inoculation  of  glycerin  extracts  of  bacterial  antigens.  The  degree  of 
reaction  was  determined  by  recording  the  diameter  in  millimeters  of  the  reactions  obtained  24  hours  after 
jnocuktion.  In  the  gonococcal  curves,  each  determination  represents  the  average  diameter  of  three 
simultaneous  tests.  The  meningococcal  curves  were  plotted  from  single  determinations.  Care  was  taken 
to  make  the  inoculation?  as  nearly  as  possible  uniform  in  depth,  and  in  the  amount  of  antigen  inoculated  . 
The  reactions  obtained  from  day  to  day  were  measured,  and  the  data  recorded  on  slips  of  paper  without 


Cutaneous  Allergy  in  Gonococcal  Infections 


8: 


DURATION  OF  CUTANEOUS  ALLERGY. 

Several  adults  tested  from  one  to  two  years  after  a  single 
gonococcal  infection  gave  positive  reactions.  A  number  of  adults 
with  a  history  of  gonorrhea  from  2  to  12  years  previously  gave 


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Chart  2. — Cutaneous  allergy  with  respect  to  gonococcal  extracts  in  a  woman,  25  years  old,  who 
acquired  gonorrhea  one  and  one-half  years  ago;  bilateral  salpingitis.  Panhysterectomy  on  April  3. 
Gonococci  were  found  in  wall  of  tube.     Rapid  recovery  after  operation. 

reactions  considerably  more  pronounced  than  the  average  normal 
adult  with  a  definite  negative  history.  Too  much  importance 
should  not  be  attached  to  the  results  in  this  latter  class  of  cases, 
as  the  possibility  of  a  persistent  gonococcal  posterior  urethritis 
or  prostatitis  was  not  excluded. 

In  arthritis  the  wave  of  immunity,  as  shown  by  cutaneous 
allergy,  may  rise  and  fall,  even  below  the  threshold  of  the  cutane- 
ous reaction,  and  it  is  probable  that  this  oscillation  occurs  as  well 
in  other  types  of  gonococcal  infection. 

A  case  of  bilateral  pyosalpinx  (Chart  2)  gave  a  positive  reac- 
tion before  operation,  and  after  panhysterectomy  the  reaction 
remained  at  the  same  height  till  the  patient  passed  out  of  observa- 
tion three  weeks  later. 


INFLUENCE    OF    OTHER    INFECTIONS    ON    THE    GONOCOCCIN 
REACTION. 

Intercurrent  diseases  such  as  whooping  cough,  chicken-pox, 
and  mumps,  in  children  suffering  from  vaginitis,  did  not  seem  to 

reference  to  previous  figures,  and  later  the  accumulated  results  were  plotted  in  cur\-es.  It  is  recognized 
that  this  method  of  recording  results  is  open  to  criticism,  particularly  in  the  matter  of  small  daily  varia- 
tions. The  more  pronounced  variations,  however,  can  hardly  be  attributed  to  errors  in  the  methods 
of  observation,  and  compare  favorably  in  point  of  accuracy  with  the  data  obtained  in  laboratory 
experiments. 


86 


Ernest  E.  Irons 


interfere  with  the  gonococcin  reaction.  Three  cases  of  gonococcal 
infection  in  persons  with  active  syphilis  gave  unusually  bright 
reactions. 

TABLE  I. 


Reaction 
S  mm.  or  More 

+ 


Reaction 
3-4  mm.  Indefi- 
nite 


Reaction 
No  Reaction 
or  2-3  mm. 


Gonococcal  arthritis 

Epididymitis 

Old  gonorrhea  1-20  years 

Ophthalmia 

Iritis 

Salpingitis 

\'aginitis,  Series  I 

Series  II 

Series  III ; . . 

Series  IV 

Normals  and  other  diseases 

Gonorrhea  denied.     No  signs 

Puerperal  sepsis  clinically  not  gonorrheal 

Fibroids — old,  cystic  ovaries,  and  endometritis 

Children— other  diseases    |  |^^.^^  jj 


Table  i  shows  the  proportion  of  positive,  negative,  and  doubt- 
ful reactions  obtained  in  some  of  the  series  of  gonococcal  infections, 
using  the  arbitrary  classification  described  above.  The  cases  are 
arranged  in  groups,  according  to  wards,  clinics,  and  hospitals. 
In  the  series  of  arthritis,  the  diagnosis  was  established  with  cer- 
tainty. The  negative  and  doubtful  reactions  were  met  with  for  the 
most  part  in  patients  with  extensive  arthritis  and  little  clinical 
evidence  of  recuperative  power.  Certain  of  these  severe  cases 
showed  first  a  negative,  and  later  a  positive  reaction  when  improve- 
ment had  set  in. 

The  several  series  of  vaginitis  show  considerable  variations  in 
the  proportions  of  positive  and  negative  cases.  This  may  be  due 
in  part  to  the  fact  that  some  series  comprised  cases  of  longer  stand- 
ing than  others,  and  in  part  to  the  fact  that  although  certain  of 
these  children  were  in  vaginitis  wards,  suffering  from  vaginitis, 
the  gonococcus  could  not  be  demonstrated'  in  the  smears  or  in 
cultures.  It  is  of  course  recognized  that  a  single  culture  from  the 
vagina  negative  for  the  gonococcus,  in  the  presence  of  many  other 
organisms,  is  b)-  no  means  conclusive  evidence  that  the  gonococcus 
is  not  present,  but  when  such  cultures  are  repeatedly  negative  for 
gonococcus,  and  show  at  the  same  time  diplococcoid  forms  of  other 


Cutaneous  Allergy  in  Gonococcal  Infections         87 

gram  negative  organisms,  one  is  led  to  wonder  whether  these  latter 
may  not  have  been  the  intracellular  gram  negative  organisms  on 


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Chart  3. — ^Cutaneous  allergy  with  respect  to  extracts  of  gonococci  in  a  girl  3  years  old,  in  whom 
gonococcal  vaginitis  with  ophthalmia  developed  as  indicated  in  the  chart. 


Enaction 

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Chart  4. — Cutaneous  allergy  with  respect  to  gonococcal  extracts  in  gonorrheal  vaginitis  in  a  girl 
2  years  old. 


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Chart  5. — Cutaneous  allergy  with  respect  to  gonococcal  extracts  Ln  recurrent  hydrops  of  the  right 


knee. 


wJiich   the  diagnosis   of  gonococcal  vaginitis  was  made   by   the 
physician.     Several  cases  of  long-standing  vaginitis  which  gave  a 


88  Ernest  E.  Irons 

persistently  negative  cutaneous  reaction  were  studied  by  means  of 
repeated  vaginal  cultures,  and  the  gonococcus  was  not  found. 
The  same  methods  and  media  gave  good  growths  of  the  gonococcus 
from  other  cases  including  vaginitis  and  urethritis.  It  seems  likely, 
therefore,  that  in  some  cases  of  vaginitis  in  specific  wards  the  gono- 
c(5ccus  is  not  present. 

In  testing  adults  who  were  supposedly  free  from  gonococcal 
infection,  several  were  found,  including  a  case  of  alcohoHc  cirrhosis, 
and  one  of  tuberculous  pleurisy,  who  gave  rather  marked  cutaneous 
reactions.  Two  of  these  were  women  in  whom  an  inactive  infec- 
tion could  not  be  excluded.  In  the  case  of  alcoholic  cirrhosis,  the 
habits  of  life  of  the  patient  were  such  that  gonococcal  infection  was 
at  least  possible. 

The  finding  of  occasional  positive  reactions  in  supposedly  non- 
gonococcal cases  and  the  failure  of  some  cases  of  arthritis  to  give 
continuously  a  positive  reaction,  suggest  the  advisabiUty  of  further 
series  of  tests,  before  absolute  reliance  is  placed  on  the  reaction  in 
diagnosis. 

In  salpingitis  of  varying  duration  (6  months  to  lo  years)  about 
50  per  cent  gave  positive  reactions.  In  the  remainder  a  faint  or 
negative  reaction  was  obtained.  This  latter  group  contained 
several  old  cases  in  which  the  record  of  operation  showed  extensive 
adhesions,  cystic  tubes,  and  ovaries  without  active  pus  formation. 
In  one  of  the  cases  giving  a  positive  reaction,  large  pus  tubes 
were  found,  from  the  walls  of  which  the  gonococcus  was  obtained 
(Chart  2). 

CUTANEOUS  ALLERGY  IN  MENINGOCOCCAL  INFECTIONS. 

Four  cases  of  epidemic  meningitis  were  studied.  A  boy  of 
two  years,  convalescent  in  the  fourth  week  after  the  onset  of  the 
infection  by  the  meningococcus,  gave  a  positive  reaction  to  gono- 
coccin.     There  was  no  sign  or  history  of  any  gonococcal  infection. 

A  youth  of  19  in  whom  there  was  no  history  or  evidence  of 
gonococcal  infection  was  tested  on  the  second  day  of  a  moderately 
severe  meningitis,  and  gave  a  negative  reaction.  Tests  on  the  sixth 
and  eighth  days  were  likewise  negative.  Four  doses  of  anti- 
meningococcic serum  had  been  given  on  the  second  to  the  fifth  days, 


Cutaneous  Allergy  in  Gonococcal  Infections 


89 


and  the  patient  was  afebrile  and  convalescent  on  the  sixth  day. 
On  the  13th  day,  the  gonococcin  i)roduced  a  reaction  of  3  to  4  mm. 
and  a  glycerin  extract  of  the  meningococcus  isolated  from  the 
patient  produced  a  reaction  of  6  mm.  The  allergy  continued  to 
increase,  and  on  the  17th  day  a  reaction  of  5  mm.  was  obtained  with 
gonococcin,  and  one  of  10  mm.  with  the  preparation  of  the  menin- 
gococcus (Chart  6). 

A  third  case  of  meningitis  in  a  man  of  30  years  was  much  more 
severe.     He  received  two  doses  of  serum  of  30  c.c.  each  on  the  second 


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Chart  6. — Cutaneous  allergy  with  respect  to  meningococcal  and  gonococcal  extracts  in  a  case  of 
epidemic  meningitis.  Antimeningococcic  serum  (30  c.c.)  given  by  lumbar  puncture  on  second,  third, 
fourth,  and  fifth  days  of  illness.  Fine  line  =  Temperature.  Heavy  broken  line  =  Reaction  to  meningo- 
coccal extracts.     Heavy  solid  line  =  Reaction  to  gonococcal  extracts. 


to  fifth  days,  became  afebrile  for  five  days  and  then  the  symptoms 
returned  with  high  fever,  headache,  etc.  On  the  13th  day  the 
reactions  to  preparations  of  the  gonococcin  and  meningococcus 
were  still  faint,  and  remained  so  until  the  19th  day,  when  they 
began  to  increase  (Chart  7). 

A  fourth  case  of  epidemic  meningitis  in  a  man  who  gave  no 
history  or  evidence  of  gonococcal  infection  showed  slightly  posi- 
tive reactions  to  gonococcin  on  the  12th  day  of  the  disease. 

Patients  with  gonococcal  infection  who  showed  a  marked  cutane- 
ous allergy  were  tested  with  the  same  antigens  as  the  meningo- 
coccal cases  described  above.  Definite  reactions  were  obtained  in 
the  gonococcal  infections  with  inoculations  of  a  preparation  of  the 
meningococcus,  though  here  the  reaction  was  less  than  that  obtained 
with  the  gonococcin. 


90 


Ernest  E.  Irons 


GROUP   REACTIONS. 

These  reactions  with  the  gonococcus  and  meningococcus  form 
a  further  demonstration  of  the  close  relationship  which  already 
has  been  shown  by  many  workers  by  comparisons  of  the  cultural 
characteristics  of  the  two  organisms,  and  by  studies  of  their  agglu- 
tinins and  precipitins.  It  is  possible  that  the  micrococcus  catarrh- 
alis  may  be  included  in  this  group  reaction,  and  infection  by  this 
organism  may  explain  the  occurrence  of  certain  doubtful  gono- 
coccin  reactions  observed  in  persons  supposedly  free  from  gonococcal 
infection. 


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Chart  7. — Cutaneous  allergy  with  respect  to  meningococcal  and  gonococcal  extracts  in  a  case  of 
epidemic  meningitis  showing  recrudescence  of  the  disease  on  the  12th  day  and  again  on  the  24th 
day,  as  shown  by  the  temperature  curve.  Antimeningococcic  serum  given  by  lumbar  puncture  as 
indicated  on  the  chart.  The  cutaneous  allergy  developed  slowly  and  to  a  relatively  slight  degree- 
Fine  line  =  Temperature.  Heavy  broken  line  =  Reaction  to  meningococcal  extracts.  Heavy  solid  line  = 
Reaction  to  gonococcal  extracts. 

Similar  group  reactions  have  been  noted  in  studies  of  the  inter- 
reactions  of  tuberculin  and  leprolin,  and  in  the  tricophytin  reaction 
in  which  antigens  prepared  from  tricophyton,  microsporon,  and 
achorion  will  all  give  reactions  in  persons  infected  with  tricophyton, 
and  the  tricophytin  will  give  reactions  in  persons  suffering  from 
favus. 


EXPERIMENTAL   ALLERGY   IN    MAN   AND    ANIMALS. 

A  man  suffering  from  a  fracture  of  the  leg,  in  whom  previous 
gonococcal  infection  was  excluded  by  careful  inquiry  into  the 
history  and  by  examination,  was  found  to  give  a  negative  cutaneous 
reaction  to  gonococcin.  He  was  then  given  repeated  subcutaneous 
injections  of  gonococcus  vaccine  and  the  subsequent  cutaneous 


Cutaneous  Allergy  in  Gonococcal  Infections 


9' 


reactions  recorded  (Chart  8).  The  maximum  reactions  were  by 
no  means  as  large  as  those  often  seen  in  infected  persons,  but 
compared  to  the  reaction  before  inoculation,  they  showed  a  definite 
increase  in  cutaneous  reactivity  following  the  injections. 

A  large  rabbit  was  given  seven  intraperitoneal  injections  of 
suspensions  of  gonococci  grown  on  rabbit's  blood  agar.  Five  weeks 
after  the  last  injection  cutaneous  tests  were  made  with  antigen  and 
control.  Shght  papules  developed  after  24  hours  at  the  site  of 
inoculation  of  the 'antigens.  The  control  inoculation  showed  no 
reaction.  This  test  was  repeated  with  the  same  result.  A  sus- 
pension from  one  blood  agar  tube  of  the  same  strain  of  gonococcus 


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Chart  8. — Cutaneous  allergy  with  respect  to  gonococcal  extracts  in  a  man  without  gonococcal 
infection  but  injected  with  killed  gonococci  as  shown  in  chart. 

was  injected  intravenously.  A  cutaneous  test  on  this  date  gave 
papules  2  to  3  mm.  in  diameter.  Two  days  later  a  reaction  of  5  mm. 
with  a  definite  hyperemia  was  obtained.  Subsequent  tests  gave 
less  marked  reactions. 


PASSIVE    ALLERGY    IN    ANIMALS. 

A  number  of  normal  guinea-pigs  (250  gms.)  and  rabbits  were 
shaved  and  cutaneous  tests  made.  In  all  animals  tested,  no  reac- 
tion beyond  that  due  to  trauma  was  obtained  either  with  antigen 
or  control. 

Four  of  the  pigs  were  then  given  intraperitoneal  injections  of 
I  c.c.  of  commercial  antigonococcus  serum.  Cutaneous  tests  after 
24  and  48  hours  were  negative. 

Two  pigs  were  given  5  c.c.  of  serum  intraperitoneally.     Tests 


92  Ernest  E.  Irons 

made  daily  for  the  succeeding  four  days  showed  nothing  beyond  an 
occasional  indefinite  papule. 

A  pig  was  given  5  c.c.  of  concentrated  antigonococcus  serum. 
On  the  following  day  the  cutaneous  test  was  entirely  negative,  but 
on  the  second  day  a  papule  of  3  mm.  was  obtained,  while  the  con- 
trol was  negative.  On  the  third  and  fourth  days  the  reaction  was 
negative. 

A  half-grown  rabbit  was  given  5  c.c.  concentrated'  antigono- 
coccus serum  intravenously.  Slight  papules  appeared  after  cutane- 
ous inoculation  on  the  second,  third  and  fourth  days. 

A  rabbit  was  given  13  c.c.  of  fluid  aspirated  from  the  knee  of  a 
patient  with  gonococcal  arthritis.  Repeated  tests  on  subsequent 
days  were  negative. 

In  these  and  similar  experiments,  the  cutaneous  reactivity 
was  apparently  slightly  increased  after  the  larger  doses  of  concen- 
trated serum,  but  the  results  were  by  no  means  marked. 

SUMMARY. 

The  cutaneous  inoculation  of  glycerin  extracts  of  autolyzed 
gonococci  in  patients  infected  by  the  gonococcus  produces  a  well 
defined  reaction.  This  reaction  is  not  usually  obtained  in  normal 
persons,  nor  in  those  suffering  from  other  infectious  diseases. 

In  persons  recently  infected,  the  reaction  is  negative  and 
increases  gradually  during  the  course  of  the  disease. 

In  the  more  chronic  forms  of  gonococcal  infection,  such  as 
arthritis,  the  degree  of  the  cutaneous  reactivity  varies  from  day  to 
day,  and  these  variations  may  be  correlated  with  the  changes  in 
the  clinical  course  of  the  disease. 

Cases  of  severe  infection,  such  as  extensive  arthritis,  may  give 
negative  reactions.  Later,  when  improvement  has  occurred,  the 
reaction  becomes  positive. 

In  general,  a  positive  reaction  is  obtained  in  patients  with  gono- 
coccal infection  at  some  time  during  the  course  of  the  disease. 

In  normal  persons   the   gonococcin  prepared  in   the  manner 

■  Commercial  antigonococcus  serum  was  concentrated  by  Dr.  P.  G.  Heineraann.  The  antibody 
content  of  the  concentrated  serum  was  estimated  by  Dr.  Gatewood  as  about  four  times  that  of  the 
original  serum,     four.  Inject.  Dis.,  1912,  10,  p.  416. 


Cutaneous  Allergy  in  Gonococcal  Infections         93 

described  gives  a  cutaneous  reaction  rarely  more  than  2  to  3  mm. 
in  diameter. 

Occasionally  in  adults  and  somewhat  more  frequently  in  chil- 
dren fairly  marked  reactions  are  met  with  where  previous  gonococcal 
infection  can  be  excluded.  In  these  cases  the  normal  antibodies 
may  be  increased  to  an  unusual  degree.  It  is  possible  that  nor- 
mal individuals  may  be  found  who  will  give  reactions  to  antigens 
prepared  from  many  pathogenic  organisms.  The  possibility  must 
also  be  borne  in'  mind  that  infection  by  one  organism  may  give 
rise  to  an  increase  in  the  proteolytic  power  of  the  serum  for  other 
organisms. 

The  cutaneous  reactions  obtained  with  meningococcal  and 
gonococcal  antigens  suggest  that  we  are  dealing  with  a  group 
reaction. 

In  diagnosis,  a  positive  reaction  is  to  be  regarded  as  confirma- 
tory evidence  of  gonococcal  infection.  Other  infections,  such  as 
those  by  the  meningococcus  or  M.  catarrhalis,  which  may  give  rise 
to  a  group  reaction,  must  be  excluded.  The  clinical  value  of  the 
reaction  must  be  determined  by  further  tests,  and  its  limitations 
defined  by  a  study  of  many  groups  of  cases. 


COLUMBIA  UNIVERSITY  LIBRARIES 

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expiration  of  a  definite  period  after  the  date  of  borrowing,  as 
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ment with  the  Librarian  in  charge. 

DATE  BORROWED 

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DATE  BORROWED 

DATE  DUE 

C2e(l14l)M100 

Ir6 
'  RC202 

Irons 


